The present invention relates to a drug delivery device and method. More particularly, the present invention relates to a drug delivery device and method that is flexible as to the drug agent employed and the duration of drug administration with an emphasis on physician control over deployment of both the drug and the device.
Obstructive atherosclerotic disease is a serious health problem facing our society today. This disease is the result of the deposit of fatty substances on the interior of the walls of the arteries. The build-up or accumulation of such deposits results in a narrowing of the inside diameter of the artery which in turn restricts the blood flow through the artery. This disease, wherein the opening or lumen of the artery is narrowed, is known as atherosclerosis and the accumulation is known as a lesion.
One commonly used procedure for treating an obstruction caused by atherosclerosis is a procedure known as coronary artery bypass graft surgery ("bypass surgery"). Although bypass surgery has been used with moderate success in the treatment of atherosclerosis, it can be extremely invasive and traumatic to the patient.
One less invasive and traumatic procedure developed more recently is coronary angioplasty. Coronary angioplasty, and angioplasty in general, is a procedure in which a balloon is positioned in the inside of the artery at the site of the accumulation or lesion and inflated in order to dilate the atherosclerotic lesion and thus open the restricted area of the artery. In order to advance the balloon to the lesion, the balloon is attached to the distal end of a small diameter catheter, which includes means for inflating the balloon from the other end of the catheter. The catheter is maneuvered or "steered" through the patient's vessels to the site of the lesion with the balloon in an un-inflated form. When the un-inflated balloon is properly positioned at the lesion, the balloon is then inflated to dilate the restricted area.
While angioplasty has been relatively successful in treating coronary artery disease, restenosis of the treated site often occurs approximately 3 to 6 months following the procedure. It is believed that the primary factor in developing restenosis is the healing that takes place after the injury caused by the intervention of the balloon dilation procedure. The restenosis has close analogy to scar formation in that the histologic result has a similar morphology. The histologic response is called intimal fibrous hyperplasia. A main result of the intimal fibrous hyperplasia consists of smooth muscle cells from the vessel wall that proliferate and migrate in the vessel wall. The net result is a thickening of the vessel wall. Over time, this thickening reoccludes or restenosis the vessel to a point where it is clinically significant. That is, the blood flow through the vessel is diminished to a rate similar to the rate before the angioplasty procedure. The occurrence of this seems to happen approximately 30-35% of the time following an angioplasty to that specific site.
Several alternative procedures have been attempted to try to affect the occurrence or rate of the restenosis following intervention to the lesion site in the coronary artery. These procedures have included the use of lasers, mechanical atherectomy devices, heated balloons, and metal implantable stents. While each of these procedures has shown some success in dealing with the initial lesion, all have the similar problem of restenosis at a similar or even greater occurrence. Current estimates of restenosis of the lesion site using these alternative procedures ranges between 40-50%. The time frame of restenosis of all of these is generally from 3-6 months after the procedure.
Therefore, it appears that this restenotic healing lesion area is independent of the type of interventional procedure used. Rather, it is a physiologic response to any type of injury brought to that lesion site. Because of this intervention independent physiologic response, it is felt by many physicians that potentially the best way to deal with restenosis would be by a pharmacologic means, such as a drug agent, targeted at the biochemical events that take place after injury.
To date, most pharmacologic trials involve either an oral or intravenously injected drug that is delivered throughout the whole body in hopes of trying to effect this small site in the arteries. This type of pharmacologic treatment is known as a "systemic treatment." Some agents that have been tried in human clinicals include: heparin, calcium channel blockers, angiotensin converting enzyme inhibitors, fish oil, and growth peptides. Other agents that may not have been tried in clinicals but am of interest include thromboxane synthetase inhibitor, serotonin antagonists, HMGCoA reductase inhibitors, platelet derived growth factors, inflammatory cell factors, platelet aggregation inhibitors, and thrombin inhibitors such as hirudin or its analogs.
The indication for use of most of these has been either in vitro cell culture studies or animal studies. These studies have shown some effect on the smooth muscle cell proliferation which is a major component of the intimal fibrous hyperplasia that takes place in the restenotic lesion. However, none of the systemic human trials to date has shown a major effect on the occurrence of restenosis.
Even though none of these agents have been completely successful in the in vivo human clinical trials, it is still generally felt that one of these agents or some other new agent, if delivered locally and site specifically to the lesion, would still be able to reduce the proliferative response. One of the problems with systemic techniques is the inability to deliver a high enough concentration of the agent locally at the lesion in order to effect the physiologic response. In the in vitro studies which have shown some success, a high concentration of the agent was used. Thus, it is believed that if the agent was delivered specifically to the site as opposed to systemically, the agent may be delivered at a high enough concentration to truly effect the physiologic response.
The reason many of these agents have not been used in a higher concentration in vivo in humans is that many of the agents may exhibit undesirable side effects. Thus, if a high concentration of the agents is given systemically, they may have unwanted physiologic effects. Therefore, if the drug can be given with high concentrations locally to the vessel wall while minimizing the systemic amount of drug, the desired result of modulating the restenotic growth while preventing any unwanted systemic effects may be achieved.
There are other ways known to date in trying to create a site specific local delivery of drug to a site. One approach presently contemplated is the use of a perforated or sweating balloon. For example, a drug delivery device is disclosed by Wolinsky, H., et al. in the article entitled, Use of a Perforated Balloon Catheter to Deliver Concentrated Heparin Into the Wall of a Normal Canine Artery, 15 JACC 475 (Feb. 1990). This device is a percutaneous transluminal coronary angioplasty (PTCA) balloon with several microholes in the balloon for delivery of an agent during balloon dilatation. The drug is incorporated into the same fluid which is used to inflate the balloon.
A major concern with any device with perforated holes is the effect of a jet stream on the wall of the blood vessel. If a balloon with holes is pressurized, a relatively high velocity and/or pressure jet stream may be ejected through the holes. There are some indications that these jet streams may cause tissue damage resulting in very severe dissection of the vessel wall after the dilatation procedure.
Another disadvantage of available devices, such as the one disclosed by Wolinsky et al., is that these devices cause a substantial blockage of blood flow in the subject vessel during the procedure. Thus, such devices may only be used for the fairly short time frame (typically, from one to two minutes), similar to the time frame of the actual angioplasty dilatation.
Other available drug delivery devices are disclosed, for example, in U.S. Pat. Nos. 4,824,436 (Wolinsky) and 4,636,195 (Wolinsky). These devices are directed to a dual occlusion catheter in which a balloon is inflated proximally and distally of the accumulation or lesion creating a space for infusion of a drug. This dual balloon catheter creates a space for infusion of drug separate from the blood flow. This device, however, also can only be used for a short period of time because it occludes blood flow.
Perfusion is very important in developing a suitable type of delivery device. It is necessary that the device provide a large latitude in time over which the agent could be delivered and therefore, devices which occlude blood flow may not provide the necessary latitude. Because the basic research into the biochemistry and physiologic events indicate that the initial events begin immediately after injury and continue intensely for several hours, it is desirable for the drug delivery system to allow drug delivery for several hours to a day or two beginning immediately after intervention. This research also points out that the initial events subsequently create a cascade of events that ultimately lead to intimal thickening. While these accumulations or lesions do not become apparent for several months, it is felt that if these initial events can be modulated, blocked, or even accelerated, then the subsequent cascade can be altered and a diminished overall thickening could be achieved.
Even in devices where the shaft tubing provides a lumen for blood flow, the blood flow is limited by the diameter of the tube. In fact, when the shaft tubing is used for a blood flow lumen, there is a competing balance of making the shaft large enough to accommodate the larger volume of blood flow while still trying to minimize the size so that the catheter can be maneuvered through the patient's vasculature. This limited blood flow, while providing obvious advantages to no blood flow, may not be completely satisfactory in providing the necessary blood flow to the heart (or other part of the body).
Catheters with expandable devices are also used in other procedures. For example, U.S. Pat. No. 4,183,102 (Guiset) discloses a device which includes a series of toroidal shaped sleeves which conform to a vessel wall. The device disclosed in this patent is for the treatment of some aortic aneurysms and does not include any means for drug delivery.
One other problem involves using existing devices when the device spans the junction point of a branch vessel (See, e.g. FIGS. 12-13). In these cases it is desirable to provide a series of drug containment spaces so that only the space that is in direct contact with the branch is drained of the drug.
Therefore, it is desirable to have a drug delivery device capable of providing the necessary blood flow to the heart for restenosis treatment. Further, such a device may also be extremely desirable in other procedures where a drug is to be delivered to a specific site in a vessel. For example, drug delivery devices may be useful in procedures where a drug or agent is used to dissolve the stenosis in an effort to avoid the use of angioplasty or atherectomy procedures altogether or to deliver a thrombolytic agent to dissolve a clot at the lesion site.
It will be recognized from this discussion that there is a need for a generic type of drug delivery system which emphasizes physician control over the device and agent. The device should have flexibility as to the agent that is to be delivered and should be capable of delivering any number of agents (either separately or at the same time), or possibly also allow a change in the protocol of the delivery. It should also be flexible with respect to the time frame over which these agents would be delivered. In order to effect this time frame of delivery, the device should also allow a large amount of blood flow by or through the device in order to maintain adequate distal perfusion of cardiac or other muscle during the delivery time.
Therefore, it is a primary object of the present invention to provide a device and method which can contain a relatively high concentration of a drug agent in a selected portion of a vessel, such as a blood vessel.
It is another object of the present invention to provide a device which can be used in a flexible time frame.
It is a further object of this invention to provide a drug delivery catheter which permits a relatively high fluid flow rate through the vessel in which it is inserted while the device is employed.
It is a still further object of this invention to provide a device which is flexible as to the drug and the number of drugs which can be delivered as well as the time frame over which they can be delivered.